Osteoporosis is endemic in the US and other Western societies and fractures are a serious medical problem among aging Veterans and their peers in the general population with 1 in 2 females and 1 in 4 males over the age of 50 projected to suffer an osteoporosis related bone fracture in their lifetimes. Fractures lead to huge healthcare expenditures, loss of mobility and significant morbidity. Hip fractures almost always require major surgery and mortality rates are extremely high in aged individuals following surgery, approaching 24% in the general population and reaching as high as 32% in male veterans. Historically, anti-resorptive drugs (such as bisphosphonates) have been the mainstay of anti-osteoporosis therapy/fracture prevention and although these agents stall further bone degeneration and lead to an increase in bone mineral density, they are inefficient at restoring high quality, remodelled bone and many patients treated with these drugs ultimately still go on to sustain a fracture. Compliance in taking anti-resorptive agents is furthermore extremely poor with multiple large population studies conducted in major healthcare systems all reporting abysmal patient compliance with typically 75% of patients discontinuing their anti-resorptive medications within a year of initiation, due to inconvenient administration schedules, side-effects and costs. Recently, rare but potentially serious complications of long term anti-resorptive use have led to hysteria among the public and an unprecedented and alarming retreat from pharmacological fracture prevention therapy is now underway. This has led to a call for action by the ASBMR leadership, however clearly, other pharmacological alternatives are now even more urgently needed. In contrast to anti-catabolic agents, drugs based on parathyroid hormone (PTH) such as Teriparatide (PTH (1-34)) and Preotact (PTH (1-84)), are the only FDA approved bone anabolic therapies capable of stimulating bone formation and reversing bone loss, thus reducing the odds of fracture. Although additional bone anabolic drugs are in development, potential side-effects have indefinitely delayed final FDA approval of Amgen?s anti-sclerostin antibody Romosozumab. PTH-based anabolics, like Teriparatide, are thus likely to remain the only available bone anabolic agents for the near future. Teriparatide however, has significant limitations of its own that have constrained its wider application, including inconvenient daily injection and rapidly waning efficacy. During the tenure of this Merit program we made the unexpected discovery that the pharmacological T cell immunosuppressant Abatacept (CTLA4-Ig), used in the therapy of inflammatory diseases, such as rheumatoid arthritis, mediates a bone anabolic signal. When Abatacept renders T cells dormant (anergic), it transforms them into Wnt10b secreting cells. Wnt10b is a ligand for the Wnt-signal transduction pathway, that promotes bone formation by stimulating differentiation and activity of osteoblasts. Teriparatide itself promotes bone formation in part by upregulating Wnt10b in T cells. We hypothesized, and demonstrated, that by priming T cells to undergo anergy, Abatacept is able to amplify the anabolic activity of Teriparatide in mice. As Abatacept alone has more modest bone anabolic activity than Teriparatide alone, our Merit renewal proposes to investigate methods to intensify the bone anabolic activity of Abatacept, Teriparatide and Abatacept and Teriparatide together. In Aim 1 we will investigate whether raising basal T cell activation state can amplify the bone anabolic activities of Abatacept and Teriparatide, alone and in combination, by enhancing the capacity of T cells to secrete enhanced concentrations of Wnt10b in response to these stimuli. In Aim 2 we will examine if Abatacept and/or Teriparatide enhance bone anabolic activity in the context of an inflammatory environment such as rheumatoid arthritis, using the collagen induced arthritis mouse model. Because T cell anergy is dependent on sustained cAMP signalling and the Wnt10b gene promoter is regulated in part through cAMP response elements (CREs), Aim 3 will examine the role of cAMP signalling in T cells and Wnt10b generation by anergic T cells.